@article{6aa87496299b40c3b2d5a1dc686cb6d8,
title = "Stabilin receptors clear LPS and control systemic inflammation",
abstract = "Lipopolysaccharides (LPSs) cause lethal endotoxemia if not rapidly cleared from blood circulation. Liver sinusoidal endothelial cells (LSEC) systemically clear LPS by unknown mechanisms. We discovered that LPS clearance through LSEC involves endocytosis and lysosomal inactivation via Stabilin-1 and 2 (Stab1 and Stab2) but does not involve TLR4. Cytokine production was inversely related to clearance/endocytosis of LPS by LSEC. When exposed to LPS, Stabilin double knockout mice (Stab DK) and Stab1 KO, but not Stab2 KO, showed significantly enhanced systemic inflammatory cytokine production and early death compared with WT mice. Stab1 KO is not significantly different from Stab DK in circulatory LPS clearance, LPS uptake and endocytosis by LSEC, and cytokine production. These data indicate that (1) Stab1 receptor primarily facilitates the proactive clearance of LPS and limits TLR4-mediated inflammation and (2) TLR4 and Stab1 are functionally opposing LPS receptors. These findings suggest that endotoxemia can be controlled by optimizing LPS clearance by Stab1.",
keywords = "Biological sciences, Immune response, Molecular biology",
author = "Fatima Cabral and Mustafa Al-Rahem and John Skaggs and Thomas, {Thushara A.} and Naresh Kumar and Qian Wu and Paolo Fadda and Lianbo Yu and Robinson, {John M.} and Jonghan Kim and Ekta Pandey and Xinghui Sun and Jarjour, {Wael N.} and Rajaram, {Murugesan V.S.} and Harris, {Edward N.} and Ganesan, {Latha P.}",
note = "Funding Information: This work is supported by NIH , United States grants AR066330 (to LPG), HL130864 (to ENH), AI146690 , AI146252 (to MVSR), and HL150536 to XS. The authors are grateful to Dr. Clark L. Anderson and Dr. Mark D. Wewers for all the intellectual contributions and critical reading of the manuscript; Dr. Beth Schachter for editorial support in the preparation of the manuscript; Dr. Robert Munford and Dr. Mingfang Lu, Laboratory of Clinical Infectious Diseases, NIAID, NIH for radiolabeled ( 3 H/ 14 C) LPS and FITC LPS; Dr. Zhili Yao for the help with live cell microscopy and preparation of labeled LPS and HDL; James M. Turman for the help with ELISA during revision; Dr. Cyrill G{\'e}raud for the anti-Stab1 and Stab2 antibodies; and Dr. Sara Cole, Richard Montione, Brian Kemmenoe, and the staff at the OSU Campus Microscopy and Imaging Facility for training and advice. Funding Information: This work is supported by NIH, United States grants AR066330 (to LPG), HL130864 (to ENH), AI146690, AI146252 (to MVSR), and HL150536 to XS. The authors are grateful to Dr. Clark L. Anderson and Dr. Mark D. Wewers for all the intellectual contributions and critical reading of the manuscript; Dr. Beth Schachter for editorial support in the preparation of the manuscript; Dr. Robert Munford and Dr. Mingfang Lu, Laboratory of Clinical Infectious Diseases, NIAID, NIH for radiolabeled (3H/14C) LPS and FITC LPS; Dr. Zhili Yao for the help with live cell microscopy and preparation of labeled LPS and HDL; James M. Turman for the help with ELISA during revision; Dr. Cyrill G{\'e}raud for the anti-Stab1 and Stab2 antibodies; and Dr. Sara Cole, Richard Montione, Brian Kemmenoe, and the staff at the OSU Campus Microscopy and Imaging Facility for training and advice. F.C. M.A.-R. J.S. T.A.T. N.K. Q.W. E.P. X.S. and E.N.H. performed the experiments. P.F. and L.Y. performed the NanoString analysis and statistical analysis of NanoString data, respectively. J.M.R. (late), W.N.J. M.V.S.R. and E.N.H. made critical contributions to the design of the project. J.K. performed the kinetic analysis. M.V.S.R. E.N.H. and L.P.G. supervised the experiments and wrote the manuscript. All authors discussed, analyzed the results, and commented on the manuscript. L.P.G. conceptualized the project. The authors declare no competing interests. Publisher Copyright: {\textcopyright} 2021",
year = "2021",
month = nov,
day = "19",
doi = "10.1016/j.isci.2021.103337",
language = "English (US)",
volume = "24",
journal = "iScience",
issn = "2589-0042",
publisher = "Elsevier Inc.",
number = "11",
}